Classical cannabinoids such as the marijuana derived cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC), as well as endogenous ligands (anandamide) produce their pharmacological effects via their agonist properties at specific cannabinoid receptors in the body. So far, two cannabinoid receptors have been characterized: CB1, a central receptor found in the mammalian brain and peripheral tissues and CB2, a peripheral receptor found only in the peripheral tissues. Compounds that are agonists or antagonists for one or both of these receptors have been shown to provide a variety of pharmacological effects. See, for example, Pertwee, R.G., Pharmacology of cannabinoid CB1 and CB2 receptors, Pharmacol. Ther., (1997) 74:129-180 and Di Marzo, V., Melck, D., Bisogno, T., DePetrocellis, L., Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action, Trends Neurosci. (1998) 21:521-528.
Over the last few years, a number of potent synthetic cannabinoid agonists have been developed. These agonist materials have helped in the characterization of cannabinoid receptors and with studies of receptor molecular properties.
Cannabinoid antagonists are compounds that bind to one of the CB1 or CB2 receptors but have no effect. There is considerable interest in developing cannabinoid antagonists possessing high affinity for one of the CB1 or CB2 receptors. Such cannabinoid antagonist materials provide a tool to better understand the mechanisms by which cannabinoid agonists produce their pharmacological effects and for the development of new therapeutic agents.
One class of cannabimimetic antagonists encompasses pyrazole derivatives. Pyrazole analogs have been found to act as antagonists for the CB1 and CB2 receptors, and occasionally to act as agonists for the CB1 and CB2 receptors. Most of the known materials show high receptor affinity for only the CB1 cannabinoid receptor. See for instance, Barth, F. et al, Pyrazole Derivatives, Method Of Preparing Them And Pharmaceutical Compositions In Which They Are Present; U.S. Pat. No. 5,624,941 to Barth et al, issued Apr. 29, 1997; Rinaldi-Carmona, M. et al, SR141716A, A Potent And Selective Antagonist Of The Brain Cannabinoid Receptor, FEBS Lett. 1994, 350, 240-244; Rinaldi-Carmona, M. et al, Biochemical And Pharmacological Characterization Of SR14171 6A, The First Potent And Selective Brain Cannabinoid Receptor Antagonist, Life Sci. 1995, 56, 1941-1947; and Makriyannis, A., Structure-Activity Relationships Of Pyrazole Derivatives As Cannabinoid Receptor Antagonists, J. Med. Chem. 42, 769-776, 1999.